Tag Archives: Parasites

Immunosuppression with Stem Cells and the Skin Fights Helminths

Mesenchymal Stem Cell
Mesenchymal Stem Cells induce an immunosuppressive response in the colon.
This week, we learn more about how mesenchymal stem cells affect the immune system, why CX3CR1 is needed to clear a yeast infection and how the body stops helminths in their tracks.

Stem Cells and Immunosuppression

A recent study on mesenchymal stem cell (MSC) therapy has uncovered a novel mechanism of immunosuppression in the colon. The French group was using MSC therapy to counter gastrointestinal complications caused during tumor radiotherapy. They found that the treatment reduced colon epithelial damage, but also reduced the relative proportion of infiltrating CD4+ and CD8+ T cells. There was also a marked reduction of T cell activation and proliferation. This downregulation was parallel with significant increases of corticosterone secretion and subsequent interleukin-10 expression.  Experiments with a glucocorticoid receptor blocker pointed towards an impaired TCR signal transduction initiated by the MSC treatment. It will be interesting to see if this finding can help improve MSC treatment of inflammatory bowel disease (IBD).

CX3CR1 and Candida

Crohn’s disease (CD) is often associated with harmful Candida albicans infections. Unlocking the secrets behind how the body controls Candida infections could be beneficial for CD patients. In this study, performed by the NIH, it was determined that the chemokine receptor CX3CR1 is crucial for macrophage survival in the kidney, the preferred hideout for Candida. During an infection, it was found that CX3CR1 was upregulated in the kidney macrophages. Mice deficient in CX3CR1 had a high mortality and were found to have uncontrolled Candida growth in the kidneys. The loss of the receptor prevented macrophages from accumulating in the kidney and engulfing the yeast. Given the growing role CX3CR1 in the pathogenesis of IBD, it will be interesting to consider if this receptor forms a link between CD and associated Candidiasis.

Helminth Induced Immune Reactions

As intestinal worms are becoming a new therapeutic for IBD, it’s interesting to learn about the immune responses that are induced upon their introduction to the body. A Japanese study in the Journal of Experimental Medicine has now shown that the skin does its best to prevent reinfection of Nippostrongylus brasiliensis. This species is similar to Necator americanus, which is used in IBD therapy. These worms enter through the skin. The scientists found that during the first exposure the skin had a limited response. However during a second application, there was a huge immune reaction, which was characterized by cellular infiltrates that trapped the larvae. The key immune cell mediating this trapping was the basophil, which detected worm antigens (bound to antibodies) using FcεRI and elicited the help of macrophages. It will be useful to determine if this process hinders worm treatment in IBD patients who have already had helminth infections.

References

Helminths and Peritoneal B Cells Reduce Colitis

Heligmosomoides
Heligmosomoides polygyrus bakeri. This murine intestinal parasite induces colon regulatory T cells.
This week reveals two interesting inflammatory bowel disease-related studies published in the Journal of Immunology. One shows how parasites can induce potent colon regulatory T cells, and the other describes the importance of peritoneal B cells in regulating inflamed intestines. For both articles, interleukin-10 plays a critical role.

Helminth Infections Induce Colon Protective Regulatory T Cells

Helminths have the ability to reduce harmful inflammation, and they are now being tested as therapeutic agents for inflammatory bowel disease in clinical trials. Using a helminth found in mice, Heligmosomoides polygyrus bakeri, scientists from Tufts attempted to learn how these parasites performed their function in the intestines. They found that the helminths increased the number of Foxp3+ regulatory T cells in the colons of host mice and increased their expression of interleukin-10 (IL-10). These regulatory T cells were capable of preventing experimental colitis in an IL-10 dependent manner.

IL-10 Expressing B Cells in the Peritoneal Cavity Modulate Colitis

B cells come in many types and are present at many locations of the body. Within the main abdominal cavity, called the peritoneal cavity, many types of B cells are found, including IL-10 producing ones called B10 cells. Scientists from Duke found that these B cells also play an important role in colitis by lowering the severity of the inflammation. The production of IL-10 by these B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, Th1 cells, and proinflammatory cytokine production.

Do you think that interleukin-10 is the über-cytokine needed to control inflammatory bowel disease? Let us know in the comments below!

References

Hang L, Blum AM, Setiawan T, Urban JP Jr, Stoyanoff KM, Weinstock JV. Heligmosomoides polygyrus bakeri Infection Activates Colonic Foxp3+ T Cells Enhancing Their Capacity To Prevent Colitis. J Immunol. 2013 Aug 15;191(4):1927-34. doi: 10.4049/jimmunol.1201457. Epub 2013 Jul 12.

Maseda D, Candando KM, Smith SH, Kalampokis I, Weaver CT, Plevy SE, Poe JC, Tedder TF. Peritoneal Cavity Regulatory B Cells (B10 Cells) Modulate IFN-γ+CD4+ T Cell Numbers during Colitis Development in Mice. J Immunol. 2013 Aug 5. [Epub ahead of print]

5 Hot Topics in Inflammatory Bowel Disease Research

Inflammatory bowel disease research, just like clothes and music, is subject to trends. To give you a good idea about where things are heading at the moment, I’ve composed a list of five hot topics in IBD research. The choices were based mainly on my own research experiences, the research prioritization report published by the Crohn’s and Colitis Foundation of America (CCFA), as well as ideas found on patient forums. 

5 Hot Topics in Inflammatory Bowel Disease Research

 

1. Microbiota

Microbiota, all of the microorganisms that colonize our bodies, takes the first spot. This topic went from obscurity to the research darling at the end of the 2000s. The first searches for the term, “gut microbiota” were in October, 2008 and were precipitated by the Human Microbiome project and the publication of a comprehensive review of human microbiota in Nature Review Microbiology. Since then, the interest has steadily risen, and in 2012, Nature even published a special on human microbiota.

Gut microbiota, without a doubt, play a role in the initiation and progress of IBD. Gut microbiota are so important to our healthy intestinal functioning that they are like an additional organ. They are important to the immunological development of our gastrointestinal tract and they regulate the development of certain types of immunity, including regulatory T cell and T helper 17 responses. Research has already shown that a number of microorganisms are able to protect from IBD, while a number of them also encourage it.

Fecal transplantation, the transplantation of healthy donor feces to IBD patients is already showing some promise for ulcerative colitis. There are also companies developing synthetic feces for transplantation. Furthermore, there is also great interest in using probiotics as treatments. Controlling microbiota in patients to optimize health will be a future step towards treating IBD.

2. Parasitic Worms

This topic is less mainstream than microbiota, however, it wins a spot due to patient interest. Joel Weinstock of the University of Iowa was the first to consider parasitic worms as being useful immunomodulators for IBD patients. In the 1990s, he realized that the loss of parasitic worms from our intestinal tracts was indirectly correlated with the rise of IBD. Even though early experiments with patients were promising, it’s only now that serious clinical trials are being performed with pig whipworms and human hookworms. Despite the slow advance of clinical studies, patients have not been deterred in seeking out parasitic worms for self-treatment. Though unregulated, providers exist that specialize in delivering worms to patients.

More research is needed to determine how they work. To make it more complicated, each type of parasitic worm has its own characteristics. In general, it is well known that parasitic worms induce T helper 2 responses, which can counteract T helper 1 and 17 responses found in IBD and increase wound repair. Some nematodes are also known to support regulatory T cell induction through secreted TGF-β mimics. Pig whipworm treatment also seems to increase the amounts of IL-22 producing T helper cells, which is known to help epithelial barrier function.

3. Innate Lymphoid Cells

Interest about these cells exploded in 2011 with the publication of an article in Nature Immunology about their involvement in the lung response during influenza infection. Until this point, they certainly were not a mainstream topic. But, it soon became apparent that they had an enormous potential to influence inflammatory responses in the gut. These cells are the primitive counter-parts to the well-known T helper subsets of the adaptive immune response. They do not possess T cell receptors or lineage markers for T cells. Instead, they are extremely sensitive to cytokine signals produced by surrounding immune cells and then secrete their own signature cytokines in return.

Studies of innate lymphoid cells in IBD patients show that their populations can be affected by disease status, and they appear to accumulate during chronic disease. This would suggest that small changes in the immunological status of patients could result in a quick response by these cells as they pump out their pro-inflammatory cytokines. Finding ways to rein in these cells could limit flaring.

4. The Brain-Gut Axis

The term “brain-gut axis” became well known in 2012, although it has been since the 80s. The concept brings to light the interconnectivity between the nerves of the gut and the functioning of the brain. In fact, many common neurological disorders like autism, Alzheimer’s disease and Parkinson’s disease are associated with intestinal issues, while IBD and IBS patients often suffer from depression and anxiety. Even more interesting is the realization that microbiota (see the first topic) appear to influence behaviour.

The pathways that connect the brain and the gut include the endocrine system with the chain of command between the hypothalamus, pituitary and adrenals as well as the neural pathway consisting of communication between the enteric nervous system with the central nervous system via the vagus nerve or sympathetic nerves. This field could deliver much needed information for prevention and treatment of IBD. It’s speculated that childhood stress and trauma could contribute to IBD susceptibility and that neurological problems may be apparent before disease onset. This concept could also lead to treatments in the form of drugs that support the anti-inflammatory actions of the nervous system.

5. Memory T cells

Learning about adaptive immune responses and memory are the mainstay of any immunology course. However, the popularity of studying memory T cells in the context of IBD isn’t all that popular. A pubmed search reveals only 149 articles with the terms “inflammatory bowel disease” and “memory T cells.” However, recent publications on this topic as well as the fact adaptive immunity is a CCFA research priority merit its inclusion on this list.

Memory T cells are created after naïve T cells are primed and expanded. They recognise antigens from the past and also remember how they should react to them. This means that they can act quickly to alert and recruit other immune cells even without the benefit of additional immune triggers like ambient cytokines or co-stimulation. In IBD, they could explain why flares can sometimes be initiated by something so simple as eating the wrong food or by other environmental changes. New findings show that bone marrow cell-derived IL-7 is able to sustain colitis-associated memory T cells and that blocking T cell traffic lowers the severity in colitis models. These findings should boost interest in this area of research.

Bonaz, B. L. B., & Bernstein, C. N. C. (2012). Brain-gut interactions in inflammatory bowel disease. Gastroenterology, 144(1), 36–49.

Broadhurst, M. J., Leung, J. M., Kashyap, V., McCune, J. M., Mahadevan, U., McKerrow, J. H., & Loke, P. (2010). IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient. Science translational medicine, 2(60), 60ra88–60ra88.

Cryan, J. F. J., & Dinan, T. G. T. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews: Neuroscience, 13(10), 701–712.

Denson, L. A., Long, M. D., Mcgovern, D. P. B., Kugathasan, S., Wu, G. D., Young, V. B., et al. (2013). Challenges in IBD Research. Inflammatory Bowel Diseases, 19(4), 677–682.

Jostins, L. L., Ripke, S. S., Weersma, R. K. R., Duerr, R. H. R., McGovern, D. P. D., Hui, K. Y. K., et al. (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119–124.

Kamada, N., Seo, S.-U., Chen, G. Y., & Nuñez, G. (2013). Role of the gut microbiota in immunity and inflammatory disease. Nature Reviews Immunology, 13(5), 321–335.

Nemoto, Y., Kanai, T., Kameyama, K., Shinohara, T., Sakamoto, N., Totsuka, T., et al. (2009). Long-Lived Colitogenic CD4+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis. The Journal of Immunology, 183(8), 5059–5068.

Walker, J. A., Barlow, J. L., & McKenzie, A. N. J. (2013). Innate lymphoid cells — how did we miss them? Nature Reviews Immunology, 13(2), 75–87.

Whelan, R. A. K., Hartmann, S., & Rausch, S. (2011). Nematode modulation of inflammatory bowel disease. Protoplasma, 249(4), 871–886.

 

 

The Curious Case of Toxoplasma gondii in Intestinal Disorders

T. gondii, a protozoan carried by cats, is known to reside in humans as well. At least 1/3 of the human population carries the cysts without even knowing it. Recent studies have shown that many more IBD patients than healthy individuals carry antibodies recognizing this pathogen, suggesting a possible association in some way. Moreover, current studies in mice show that T. gondii can wreak havoc in the intestines during initial exposure to the parasite leading to the loss of Paneth cells.  As Paneth cells are crucial for keeping intestinal bacteria under control, their loss also leads to an overgrowth.

Main points:

  • T. gondii antibodies are found in IBD patients.
  • T. gondii via TLR11 causes T cells to release huge amounts of IFNγ that leads to the death of Paneth cells in mice.
  • The loss of Paneth cells leads to changes in the microbiota and intestinal inflammation.
  • Humans do not express TLR11, but they could recognize T. gondii via TLR7 or TLR9.

Take home message: The possibility exists that T. gondii infections could complicate or even help initiate IBD in certain individuals.

A recent Journal of Autoimmunity article found that antibodies directed towards T. gondii were more prevalent in IBD patients than in controls. This suggests that T. gondii, a primitive protozoan, could be involved in the pathology of IBD. As up to 1/3 of the human population is often latently infected with T. gondii, this sparked my interest and a quick look at the recent literature about T. gondii revealed that this protozoan isn’t going unnoticed in the intestines (at least in mice that is…).

TIBDI post 4 finalT. gondii is well known for its ability to be spread through cat feces. Indeed, cats are its primary host and is the only mammal in which it reproduces (produces oocysts). T. gondii’s lifecycle consists of first being excreted as an oocyst in cat feces, which are, through various means, ingested by other mammals. In mammals, other than cats, T. gondii can survive as cysts within nervous or muscle tissue, often without the host noticing anything. Mice, which are considered secondary hosts, do not secrete the oocysts in their feces, but are great spreaders of T. gondii because the cysts they carry in their bodies can infect cats when they are caught and eaten.

Mice are efficient at keeping the latent T. gondii under control and show no signs of the infection. However, during acute toxoplasmosis, they do develop an acute immune response that, interestingly enough, includes an intestinal dysbiosis, especially in the area of the ileum.

It is this intestinal pathology that was the focus of a recent article found in Nature Immunology. The authors were interested in finding out more about the immune processes associated with the development of the intestinal disorder. They discovered that the pathology was related to the production of IFNγ by T cells, particularly CD4+ T cells, which would lead to the destruction Paneth cells.

Paneth cells are particularly important cells found in the crypt regions of the intestines. They produce anti-microbial peptides, which keep the crypts free of bacteria. If they die, then intestinal bacteria are free to enter the deep folds of the intestinal surface. This can lead to unwanted interactions between bacteria and bacterial sensing receptors (such as Toll-like receptors (TLRs)) and can, ultimately, cause inflammation.

In the case of the T. gondii-infected mice, it appears that this is happening, and it is a part of the reason that the intestinal problems occur. Their results indicated that recognition of T. gondii through a MyD88 (an adaptor molecule for TLR signaling) dependent cascade in T cells caused a huge release of IFNγ that lead to mitochondrial-damage-induced death of Paneth cells. The loss of these Paneth cells then caused the loss of crucial anti-microbial peptide production and subsequent bacterial over growth. In this environment, they detected that the intestinal flora composition changed and was predominated by the Enterobacteriaceae family of Gram-negative bacteria. These bacteria were not bystanders and their presence was necessary for the intestinal symptoms including the loss of Paneth cells.

This story is fascinating, but has a chicken and the egg problem. If Enterobacteriaceae bacteria are necessary for the loss of Paneth cells, how can it be necessary that the loss of Paneth cells is needed for their abnormal overgrowth? It must be that the combination of T. gondii infection plus normal interactions with Enterobacteriaceae is causing the problem.

The authors do address this somewhat in the discussion and say that it must be a combination of activation of TLR11 and other TLRs that is doing the trick. TLR2, which recognizes Gram-negative bacteria, would be such a candidate. They do find that TLR11-/- mice are partially protected from the intestinal problems, suggesting that TLR11 plays a predominant role. However, they do not check to see if TLR11 is actually the main TLR being triggered on the T cells or even investigate its expression on different immune cells.

Incidentally, TLR11 is not even produced in humans, which would make one wonder how relevant this study actually is for humans. In fact, a recent study in Cell Host & Microbe explains that two alternative TLRs in mice, 7 and 9, recognize RNA and DNA of T. gondii, respectively. They also found that in human cells, this method of T. gondii recognition via nucleic acids is particularly potent.

It is interesting to consider that T. gondii may play a role in IBD. However, intestinal problems are not the most common symptom for human infected with T. gondii. Though the number of IBD patients producing antibodies that recognize T. gondii is significantly higher than healthy controls, the number is still very low (8% of patients react to T. gondii as opposed to 1% in the normal population). Still, it could be that those 8% have just the right genetic background that when exposed to T. gondii produces just the right conditions for the disease to develop. Only further research will answer that question.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

Sources

Andrade, W. A., do Carmo Souza, M., Ramos-Martinez, E., Nagpal, K., Dutra, M. S., Melo, M. B., et al. (2012). Combined Action of Nucleic Acid-Sensing Toll-like Receptors and TLR11/TLR12 Heterodimers Imparts Resistance to Toxoplasma gondii in Mice. Cell Host & Microbe, 1–12. doi:10.1016/j.chom.2012.12.003

Raetz, M., Hwang, S.-H., Wilhelm, C. L., Kirkland, D., Benson, A., Sturge, C. R., et al. (2012). Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-gamma-dependent elimination of Paneth cells. Nature Immunology, 1–9. doi:10.1038/ni.2508

Shapira, Y., Agmon-Levin, N., Selmi, C., Petríková, J., Barzilai, O., Ram, M., et al. (2012). Prevalence of anti-toxoplasma antibodies in patients with autoimmune diseases. Journal of Autoimmunity, 39(1-2), 112–116. doi:10.1016/j.jaut.2012.01.001